Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting over 2 million Americans. In addition to the associated increase in morbidity and risk for stroke, recent data from the Framingham Heart Study (2) indicated that subjects with AF have markedly reduced survival compared with subjects without AF even after adjustment for preexisting cardiovascular conditions. A possible explanation for the increased mortality could be the autonomic changes that accompany this arrhythmia and the effects of AF on the electrophysiologic properties of the ventricles. We have recently shown for the first time that induced AF was associated with an increase in sympathetic nerve activity (SNA). The first aim of this proposal is to assess the effect of persistent AF on SNA. We hypothesize that persistent AF is associated with an increase in SNA (Hypothesis 1). In addition, we hypothesize that the increase in SNA is directly correlated with arterial baroreflex gain (A-BRG)(Hypothesis 2A) and inversely correlated with cardiopulmonary baroreflex gain (CP- BRG)(Hypothesis 2B). The second aim of this proposal is to assess the effects of AF on the electrophysiologic properties of the ventricles. In specific, we will be assessing the effect of persistent AF and an irregular ventricular sequence on ventricular repolarization and dispersion of refractoriness. We hypothesize that persistent AF results in an increase in ventricular refractoriness and dispersion of refractoriness (Hypothesis 3), and that these electrophysiologic changes are primarily due to the irregular ventricular response (Hypothesis 4). Hypothesis 1, and 2A&B, will be tested in Studies 1 and 2 in patients undergoing AF cardioversion where SNA will be measured before and after cardioversion, in addition to measuring A-BRG and CP-BRG. Hypothesis 3 will be tested in study 3 in patients who underwent successful cardioversion. QTc, QT dispersion, mean ventricular action potential duration, dispersion of repolarization, and restitution of repolarization will be performed Day-0 and Day 30 post-cardioversion. Hypothesis 4 will be tested in Study 4 in patients undergoing an electrophysiologic study. Patients will be randomized to 30 minutes of regular or irregular atrio-ventricular sequential pacing and measurements of right ventricular effective refractory period, QTc, QT dispersion, mean ventricular action potential duration, dispersion of repolarization, and restitution of repolarization will be assessed before and after pacing. If our hypotheses are true, then by changing both the "milieu" and the "substrate", AF could lead to increased ventricular arrhythmias in patients with heart failure. The results of our studies could explain the increased mortality associated with AF and should have a great impact on our management of patients with AF and heart failure. [unreadable] [unreadable] [unreadable]